Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects

Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest genetic risk factor for Parkinson's disease (PD). Communication between gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking the Gba1b gene, the main fly orthologue of GBA1, display widespread innate immune up-regulation, including gut inflammation and brain glial activation. We also demonstrate gut dysfunction in flies lacking Gba1b, with increased intestinal transit time, gut barrier permeability and microbiome dysbiosis. Remarkably, modulating the microbiome of Gba1b knockout flies, by raising them under germ-free conditions, can partially ameliorate lifespan, locomotor and some neuropathological phenotypes. Lastly, direct stimulation of autophagy by rapamycin treatment achieves similar beneficial effects. Overall, our data reveal that the gut microbiome drives systemic immune activation in Gba1b knockout flies and that reducing innate immune response activation either by eliminating the microbiota or clearance of immunogens by autophagy may represent potential therapeutic avenues for GBA1-associated neurodegenerative disease.